Opioids are powerful pain killers and are highly addictive. Opioid dependence affects nearly 5 million people in the United States and leads to approximately 17,000 deaths annually. According to the CDC, rates of opioid overdose deaths jumped significantly, from 7.9 per 100,000 in 2013 to 9.0 per 100,000 in 2014, a 14% increase. In 2015, opioid-involved drug overdoses accounted for 33,091 deaths, approximately half involving prescription opioids.
The treatment of pain and patients' access to needed opioid analgesics has always been in conflict with preventing the misuse and abuse of these potentially addictive medications. With prescription drug abuse growing to epidemic proportions in the United States, it is now becoming significantly important to find effective solutions that lower abuse.
Opioid abusers typically tamper with opioid products in order to extract the active drug which is then smoked, inhaled, or injected intravenously (Webster, Pain Med. 10:S124 (2009)). The opioids most likely to be abused are those with long-acting (LA) or extended-release (ER) formulations because each tablet or capsule contains approximately 4 times more opioid than their short-acting or immediate-release (IR) counterparts (see Table 1). The active agent in the ER product is extracted for inhalation, smoking, or injection (Katz et al, Am. J. Drug Alcohol Abuse 37:205 (2011)). This involves manipulating the product (typically crushing it, pulverizing it, or dissolving it in solution for use in a syringe) and may also involve chewing the product in an effort to defeat the ER mechanisms. One mode of abuse involves crushing a dosage form (e.g., using a pill crusher, coffee grinder, or hammer) and inhaling or snorting the resultant powder. Another mode of abuse involves extracting the active ingredient with water, alcohol or another solvent or healing the drug to transform it into a liquid to produce a liquid form for injection.
TABLE 1Comparison of API quantity present in immediaterelease and controlled releaseMaximum Strength(API in the dosage form)DrugImmediate releaseControlled releaseOxycodone Hydrochloride30mg80mgHydrocodone Bitartrate10mg50mgMorphine SulfateNot available200mgHydromorphone Hydrochloride8mg32mgOxymorphone Hydrochloride10mg40mg
Technologies have been developed to produce ER opioid formulations designed to resist or deter abuse by making these products harder to crush or dissolve. These so-called abuse-deterrent formulations (ADFs) are now recognized as important tools for the prevention of opioid misuse and abuse, although they cannot completely prevent all abuse. The following products have been approved by the FDA and arc currently in the US market.
TABLE 2FDA approved ADF productsProductAbuse-deterrent propertyFDA approval dateOXYCONTIN ®Mechanical resistance2010 (original(oxycodone CRGelling in solventsformulation:tab)†December 1995)NUCYNTA ® ERMechanical resistance2011(tapentadol ER tab)EXAGLO ®OROS technology, hard2010(hydromorphoneouter shellER tab)Gelling in solventsOPANA ® ERCrush resistant2011(oxymorphone“Intac technology”ER tab)by GrunenthalOXECTA ®Gels in liquid2011(oxycodone tab)Nasal irritant“Aversion technology”by Acura Pharma-ceuticalsEMBEDA ™Mixed agonist/antagonist2009 (Voluntarily(morphine/naltrexoneSequestered antagonistRecalled MarchER cap)“Intac technology”2011 and relaunchedby Grunenthalin 2014)HYSINGLA ® ERMechanical resistance2015(hydrocodoneGelling in solventsER tabs“Intac technology”by GrunenthalMORPHABOND ® ERMechanical resistance2015(Morphine ER tab)Gelling in solventsSentryBond ™Technology by InspironDelivery ScienceXTAMPZA ® ERMechanical resistance2016(oxycodone ER Caps)due to fatty acidsDetrex Technology byCollegiumTROXYCA ® ERMixed agonist/antagonist2016(oxycodone ER/Sequestered antagonistNaltrexone Caps)ARYMO ® ERMechanical resistance2017(morphine ERGelling in solventstabs)VENTRELA ® ERGelling in solvents2017(hydrocodone ER tab)ROXYBOND ® ERMechanical resistance2017(oxycodone IR tab)Gelling in solventsSentryBond ™Technology by InspironDelivery Science
Various abuse reducing approaches arc known in the prior art. Approaches based on physical barriers include the following. U.S. Pat. No. 9,132,096 discloses an abuse deterrent dosage form using beads for active ingredient and another set of beads containing gelling agent. U.S. Pat. No. 8,901,113 discloses an abuse deterrent dosage form wherein an active ingredient is combined with a polymer (gel forming agent) to form a matrix. U.S. Pat. No. 8,647,669 discloses a dosage form comprising a drug loaded in a resin and a trap comprises a gelling agent, the TPTA trap comprising a TPTA trap activator, wherein the dosage form comprises a multiplicity of subunits and/or layers. U.S. Pat. No. 9,044,398 discloses an abuse deterrent dosage form made by forming micro-particles of a drug modified to increase its lipophilicity. The abuse-deterrent composition retards the release of drug, even if the physical integrity of the formulation is compromised. U.S. Pat. No. 8,420,056 discloses a solid administration form, comprising at least one synthetic or natural polymer having a breaking strength of at least 500 N in addition to one or more active substances. U.S. Pat. No. 9,044,402 discloses a controlled release dosage form using polyethylene oxide (PEO) having an average molecular weight of from about 400,000 daltons to about 600,000 daltons along with opioids such that the tablet composition does not provide immediate release of the opioid even after the abuse-deterrent tablet is subjected to physical tampering selected from crushing, grinding, grating, cutting, or crisping, and wherein the tablet composition exhibits a viscosity of at least 170 mPas. U.S. Pat. No. 8,652,529 discloses solid microparticulate oral pharmaceutical forms having a coating layer which assures modified release of the active principle and simultaneously imparts crushing resistance to the coated particles so as to avoid misuse. U.S. Pat. No. 9,101,661 discloses a controlled release dosage form comprising two different molecular weights of polyethylene oxide and its manufacturing process, by which it is abuse resistant from crushing, alcohol extraction and dose dumping to discourage an abuser from tampering with the dosage form.
Approaches using agonist/antagonist combinations include the following. U.S. Pat. No. 7,682,634 discloses a controlled release dosage form comprising an antagonist, an agonist, a seal coat, and a sequestering polymer, wherein the antagonist, agonist, seal coat and at least one sequestering polymer are all components of a single unit, and wherein the seal coat forms a layer physically separating the antagonist from the agonist. U.S. Pat. No. 9,456,989 discloses a sequestered opioid antagonist along with the releasable opioid agonist using hydrophobic polymers for the sequestered antagonist non releasable naltrexone part as coaled beads and uses pH independent beads for the agonist part of the dosage form. U.S. Pat. No. 8,182,836 discloses an opioid antagonist layer coated on an biologically inert pellet, wherein the opioid antagonist layer comprises a therapeutically effective amount of an opioid antagonist; and a non-releasing membrane coated on the opioid-antagonist layer and other beads that have controlled release agonist.
The above patents describing a physical barrier for an abuse deterrent are prone to chemical extraction of the opioid drug. The above patents with sequestered antagonist were coated with a hydrophobic polymer or a polymer that makes the antagonist or naltrexone non-releasable with a controlled release coating whereas the releasable agonist or opioid drug part is made with another or a different polymer than that used to coat the antagonist. Again, this approach means the opioid drug can be extracted using a solvent that dissolves only the polymer in the opioid releasable part whereas the solvent docs not dissolve the polymer coating the non-releasable or sequestered antagonist part.
The abuse deterrent performance of marketed dosage forms has been disappointing. Post-market testing results for oral drug abuse potential are shown in Table 3. The table indicates the data from the oral abuse potential study of FDA approved abuse deterrent formulations from different opioid products. All the products are prone to abuse by the oral route. EMBEDA™ and TROXYCA® contain agonist along with the antagonist as capsules. The antagonist is coated on sugar beads and seal coated by a non-permeable polymer and agonist is coated on top of the antagonist beads coat with a permeable polymer. FDA review has indicated that a certain solvent can extract only the agonist and the dosage form can be abused. The solvent extraction effect has been shown in FDA approved naltrexone sequestered products. EMBEDA™ contains 0.4 mg of naltrexone/5 mg of morphine and TROXYCA® has 0.6 mg of naltrexone/5 mg of oxycodone. Based on the oral abuse potential study, the naltrexone concentration in both products does not deter the abuse potential by the oral route.
TABLE 3Post-market studies evaluating the oral abuse potential of ADFsVAS score, EmaxTakeOverallIntact & crushedDrugdrugdrugADF (n)DoseADFs & activelikingagainlikingExtended-release (ER)No oral abuse potential studyOXYCONTIN ®χTAMPZA ® ER40mgXtampza ER- intact68.870.269.4(n = 38)Xtampza ER- crushed73.473.774.2IR oxycodone- crushed81.875.476.2TROXYCA ® ER60mgTroxyca ER- intact59.348.753.3(n = 4.1)Troxyca ER- crushed74.572.574.3IR oxycodone- crushed89.881.581.8TARGINIQ ™ ER—Targiniq ER-intact54.738.5NR(n = 29)Targiniq ER-chewed54.632.6NROxycodone IR solution77.961.4NRHYSINGLA ® ER60mgHysingla ER- intact63.332.654.9(n = 35)Hysingla ER- crushed694356.8Hydrocodone IR solution9486.784.1VENTRELA ® ER45mgVantrela ER- intact53.946.449.2(n = 41)Vantrela ER- crushed66.958.759Hydrocodone IR85.275.275EMBEDA ™120mgEmbeda- crushed65.257.758.6(n = 33)Morphine sulfate80.870.769.8ER- crushedEMBEDA ™120mgEmbeda- intact67.6NRNR(n = 32)Embeda- crushed68.1NRNRMorphine solution89.5NRNRMORPHABOND ® ERNo oral abuse potential studyARYMO ® ER60mgArymo ER- intact625657(n = 38)Arymo ER- crushed6761.563.5Morphine sulfate746867.5ER- crushedSource: Institute for clinical and economic review 2017
In EMBEDA™, the antagonist naltrexone, which is sequestered in the core of each bead, remains latent if the drug is taken as prescribed. However, if the beads are crushed, the antagonist is released and reduces the effects of the morphine. A Phase III trial demonstrated efficacy in pain relief. Data released in the abstract indicate that the morphine pharmacokinetic profile of EMBEDA™ crushed and swallowed is similar to that of immediate-release morphine, but in liking studies EMBEDA™ crushed is “liked” no more than EMBEDA™ taken whole. Co-ingestion of alcohol may result in an increase in plasma levels and potentially fatal overdose of morphine.
These data clearly indicate that currently FDA approved products do not offer adequate oral abuse deterrent properties. This data also indicate that 0.4 mg or 0.6 mg of naltrexone/5 mg of an opioid is insufficient to act as an abuse deterrent in agonist/antagonist combination products. A higher dose of naltrexone is required to act as an abuse deterrent. The current FDA approved dose of naltrexone for opioid abuse deterred is 25 mg to 150 mg naltrexone tablets. Other products like OXYCONTIN®, MORPHABOND® and ARYMO® extended release tablets using other technologies also do not deter the abuse potential by the oral route.
All of the FDA approved extended release opioid products have a warning on the label indicating that these opioid products should not be taken with alcohol. It is also reported in the clinical data of TROXYCA® ER capsules in 40% alcohol showed a 6.4-fold higher Cmax, OPANA® ER a 2.7-fold higher Cmax, NUCYNTA® ER a 4.38-fold higher Cmax, and EMBEDA™ ER a 5-fold higher Cmax.
The data from the oral abuse potential study and the alcohol dose dumping study on FDA approved abuse deterrent products shows clearly that there is a need for improved abuse deterrent opioid formulations required to prevent opioid abuse deaths. A need still exists for an effective treatment of pain with opioids and other abuse potential drugs which are non-extractable with higher patient compliance and deterrence of the abuse potential.